| First Author | Schnell SA | Year | 2015 |
| Journal | Blood | Volume | 125 |
| Issue | 18 | Pages | 2806-14 |
| PubMed ID | 25784680 | Mgi Jnum | J:222282 |
| Mgi Id | MGI:5644225 | Doi | 10.1182/blood-2014-10-608448 |
| Citation | Schnell SA, et al. (2015) Therapeutic targeting of HES1 transcriptional programs in T-ALL. Blood 125(18):2806-14 |
| abstractText | Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1-induced leukemogenesis strictly required for tumor cell survival. Mechanistically, we demonstrate that HES1 directly downregulates the expression of BBC3, the gene encoding the PUMA BH3-only proapoptotic factor in T-cell acute lymphoblastic leukemia. Finally, we identify perhexiline, a small-molecule inhibitor of mitochondrial carnitine palmitoyltransferase-1, as a HES1-signature antagonist drug with robust antileukemic activity against NOTCH1-induced leukemias in vitro and in vivo. |
